The chemistry and pharmacology of nitroxybutylester ((CH.sub.2).sub.4 --ONO.sub.2) derivatives of several aryl propionic acid nonsteroidal antiinflammatory compounds, including ketoprofen, flurbiprofen, suprofen, indobufen and etodolac, was described in PCT Application No. WO 94/12463. Studies on nitroxybutylester derivatives of flurbiprofen and ketoprofen are also reported in Wallace et al, Gastroenterology, 107:173-179 (1994). See, also, Cuzzolin et al, Pharmacol. Res., 29(1):89-97 (1994); Reuter et al, Life Sci. (USA), 55/1(PL1-PL8) (1994); Reuter et al, Gastroenterology, 106(4):Suppl. A759 (1994); Wallace et al, Eur. J. Pharmacol., 257(3):249-255 (1994); Wallace et al, Gastroenterology, 106(4):Suppl. A208 (1994); and Conforti et al, Agents-Actions, 40(3-4):176-180 (1993). These publications uniformly examine and rely upon the use of indirectly linked nitrogen dioxide substitutions. U.S. Pat. No. 5,703,073 describes nonsteroidal antiinflammatory compounds containing a nitrogen monoxide group indirectly linked to the nonsteroidal antiinflammatory compound and their protection against gastrointestinal, renal and other toxicities normally induced by nonsteroidal antiinflammatory compounds. The compounds described in U.S. Pat. No. 5,703,073 all contain a heteroatom flanked by a carbonyl group in the form of an ester, amide or thioester in the main chain of the linker.
The use of nonsteroidal antiinflammatory compounds for the treatment and/or prevention of ophthalmic diseases or disorders such as glaucoma, inflammations of the eye and elevation of intraocular pressure has been described. For example, U.S. Pat. No. 5,474,985 describes the use of nonsteroidal antiinflammatory compounds to treat or prevent non-inflammatory induced, elevated intraocular pressure associated with the administration of corticosteroids; U.S. Pat. Nos. 5,674,888 and 5,599,535 describe the use of nonsteroidal antiinflammatory compounds to treat loss of trabecular meshwork resulting from aging, exposure to toxic substances, environmental stresses, such as oxidative or phagocytic injury, or glucocorticoid exposure; U.S. Pat. No. 5,814,655 describes topical ophthalmic compositions comprising nonsteroidal antiinflammatory compounds; Wiederholt et al., Invest. Opthalmol. Vis. Sci., 2515-2520 (1994) describes the use of nitric oxide donors to relax trabecular meshwork and ciliary muscle; Behar-Cohen et al., Invest. Opthalmol. Vis. Sci., describes the use of nitric oxide donors to decrease intraocular pressure.
There is a need in the art for nonsteroidal antiinflammatory compounds that do not have the adverse side effects associated with prior art compounds. There is also a need for new and improved treatments of inflammatory diseases states and disorders; and ophthalmic diseases and disorders. The present invention is directed to these, as well as other, important ends.